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Abstract

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut–immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.

Weber, M. A.et al.Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J. Hypertens.32, 3–15 (2014)

Acknowledgements

We thank G. N’diaye, I. Kamer, S. Seubert, P. Voss, J. Anders, C. Schmidt, A. Geuzens, R. Hercog and S. Kandels-Lewis for assistance; and J. J. Mullins and F. C. Luft for their support. This study was funded by grants from the German Centre for Cardiovascular Research (DZHK; BER 1.1 VD), the Center for Microbiome Informatics and Therapeutics, and the MetaCardis consortium. D.N.M., J.J. and M.G. were supported by the German Research Foundation (DFG). R.A.L. holds an endowed professorship supported by Novartis Pharma. M.K. was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (640116), by a SALK-grant from the government of Flanders, Belgium and by an Odysseus-grant of the Research Foundation Flanders (FWO), Belgium. L. reuteri was provided by L. Romani.

Author information

Author notes

Ralf A. Linker

, Eric J. Alm

& Dominik N. Müller

These authors jointly supervised this work.

Affiliations

Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany

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Contributions

N.W. led and conceived the project, designed and performed most experiments, analysed and interpreted the data. M.G.M., S.W.O. and S.M.K. performed 16S sequencing and data analysis. S.H., D.T., M.Ba. and C.W. performed animal experiments and analysed data. H.B., S.H., A.B., D.A.G. and B.F.C.-R. performed and analysed flow cytometry. L.Mai., S.M.K., V.S., P.N. and R.G.G. performed bacterial growth experiments. O.V. and C.F. performed metabolite analysis with input from A.B. and M.G.M. L.Mar., F.H.K. and L.K. performed 16S qPCR. N.R. performed sodium analyses. K.F. performed metagenomic analyses with contributions from P.I.C. and S.S. M.Bo., R.D. and A.M. conducted the clinical study. A.K. performed statistical analyses. M.G., A.T., J.M.T., S.K., P.B. and J.J. supervised the experiments and analyses. D.N.M., E.J.A., M.K. and R.A.L. conceived the project, supervised the experiments and interpreted the data. N.W. and D.N.M. wrote the manuscript with key editing by E.J.A., R.A.L., M.K. and K.F. and further input from all authors.

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Editorial Summary

Gut microbes worth their salt

The role of the gut microbiota in human disease is becoming increasingly recognized. In this study, Dominik Mller and colleagues report that a diet high in salt alters the composition of the gut microbiota in mice, causing pronounced depletion of the commensal Lactobacillus murinus and reduced production of indole metabolites. Previous work has suggested that a high salt diet leads to the generation of pathogenic T helper 17 (TH17) cells, which have been linked to hypertension and autoimmunity. The authors show that treatment of mice on a high salt diet with L. murinus prevents salt-induced aggravation of actively induced autoimmune encephalomyelitis and salt-sensitive hypertension, through the suppression of TH17 cells. In a pilot study in a small number of humans, the authors also show that high-salt challenge induces an increase in blood pressure and TH17 cells, associated with a reduction in Lactobacillus in the gut. However, future work is required to determine whether the findings for mice are translatable to humans.